Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].C1N=CN([C:14](N2C=NC=C2)=[O:15])C=1.[NH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][O:29][C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])[CH2:24][CH2:23]1>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:14]([NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][O:29][C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])[CH2:24][CH2:23]1)=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC1CCC(COC(=O)N2CCCC2)CC1
Reactant: OCc1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCC(COC(=O)N2CCCC2)CC1)OCc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a solution of pyrrolidine-1-carboxylic acid 4-oxo-cyclohexylmethyl ester (2 mmol) in ethanol (10 mL) was added hydroxylamine (10 mmol) and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide pyrrolidine-1-carboxylic acid 4-hydroxyimino-cyclohexylmethyl ester. Pyrrolidine-1-carboxylic acid 4-hydroxyimino-cyclohexylmethyl ester was dissolved in a 2N ammonia methanol solution (10 mL) and then Raney nickel was added. After 12 hours stirring under hydrogen atmosphere, the reaction mixture was filtered and concentrated under reduced pressure to provide pyrrolidine-1-carboxylic acid 4-amino-cyclohexylmethyl ester. To a solution of pyridine-2-yl-methanol (2 mmol) in THF (10 mL) was added CDI (2 mmol). After 2 h stirring at room temperature, pyrrolidine-1-carboxylic acid 4-amino-cyclohexylmethyl ester was added and the resulting mixture was stirred for additional 2 hours at 60° C. The reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, ethyl acetate), thereby completing the preparation of a target compound (310 mg, 43% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[F:24])[CH:8]=1.[CH3:26][N:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28](=[O:33])[CH2:29][C:30](O)=[O:31].C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:30](=[O:31])[CH2:29][C:28]([N:27]([CH3:26])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:33])=[CH:19][C:18]=2[F:24])[CH:8]=1
Reactant: CN(C)CC/C=C\c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: CN(C(=O)CC(=O)O)c1ccccc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CC/C=C\c1cc2nccc(Oc3ccc(NC(=O)CC(=O)N(C)c4ccccc4)cc3F)c2s1
Reaction time: 6 h
Yield: 34.2 %

Procedure:
A solution of (Z)-4-(2-(4-(dimethylamino)but-1-enyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (235) (69.1 mg, 0.193 mmol), 3-(methyl(phenyl)amino)-3-oxopropanoic acid 31 (46 mg, 0.26 mmol) (scheme 10), and EDC (45 mg, 0.24 mmol) in DMF (2.8 mL) was stirred overnight at room temperature. More 31 (45 mg, 0.26 mmol) and EDC (45 mg, 0.24 mmol) were added and the mixture stirred 6 h more. The mixture was diluted with EtOAc, washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was redissolved in MeOH and purified twice by preparative HPLC (gradient 40% to 95% MeOH in water, 45 min) giving title compound 231 (35 mg, 0.066 mmol, 34% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.32 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 7.80 (d, J=12.7 Hz, 1H), 7.54 (s, 1H), 7.5-7.3 (m, 7H), 6.78 (d, J=12.2 Hz, 1H), 6.62 (d, J=5.5 Hz, 1H), 5.92 (tt, J=7.2 Hz, J=4.5 Hz, 11.7 Hz, 1H), 3.21 (s, 5H), 2.59 (m, 2H), 2.42 (dd, 6.8 Hz, 7.4 Hz, 2H), 2.16 (s, 6H). MS (m/z): (M+1) 533.1 (100 N.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].O[CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:24](=[O:38])[NH:25][C:26](=[O:37])[C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])=[CH:15]1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([O:5][CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:24](=[O:38])[NH:25][C:26](=[O:37])[C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])=[CH:15]1)(=[O:4])=[O:3]
Reactant: O=C1NC(=O)C(c2cn(CCCO)c3ccccc23)=C1c1ccccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
93 mg of methanesulphonic anhydride were added to a solution of 0.46 mmol of the product of Example 55 in 25 ml of dichloromethane. 0.5 ml of pyridine was added and the mixture was stirred for 0.5 hour, then washed with water, dried and concentrated. Chromatography of the residue on silica gel with 10% methanol in dichloromethane gave 160 mg of 3-[1-[3-(methylsulphonyloxy)propyl]-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 177°-178° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[N:18]=3)[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:25]=[C:12]2[C:13](=[O:24])[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:26]4[CH2:28][CH2:27]4)[N:18]=3)[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: O=C1c2cc(OCc3ccccc3)nn2CCN1c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: O=C1c2cc(OCc3ccccc3)nn2CCN1c1cccc(C2CC2)n1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (14.5 mg, 0.013 mmol) was added to a stirred suspension of 2-(benzyloxy)-5-(6-bromopyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.1 g, 0.25 mmol), cyclopropylboronic acid (0.043 g, 0.5 mmol) and K2CO3 (0.104 g, 0.013 mmol) in a mixture of 1,4-dioxane (1 mL) and DMF (1 mL). The mixture was stirred at 150° C. for 15 minutes under microwave irradiation. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, washed with a saturated solution of NaCl, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected, the solvents evaporated in vacuo and the residue triturated with DIPE to yield 2-(benzyloxy)-5-(6-cyclopropylpyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (41 mg, 45% yield) as a pale yellow solid. C21H20N4O2. 1H NMR (500 MHz, CDCl3) δ ppm 0.92-1.03 (m, 4H), 1.97-2.05 (m, 1H), 4.31 (dd, J=6.6, 5.2 Hz, 2H), 4.50 (dd, J=6.9, 5.2 Hz, 2H), 5.23 (s, 2H), 6.37 (s, 1H), 6.99 (d, J=6.9 Hz, 1H), 7.31-7.36 (m, 1H), 7.36-7.42 (m, 2H), 7.46 (d, J=7.2 Hz, 2H), 7.57 (t, J=7.9 Hz, 1H), 7.76 (dd, J=8.4, 0.6 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9]Cl.[CH:11]1([NH:14][C:15](=[O:41])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[OH:39])([CH3:32])[CH3:31])[C:24]3=[O:40])[CH:17]=2)[CH2:13][CH2:12]1.[C:42](#[N:44])C>>[CH:11]1([NH:14][C:15](=[O:41])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([CH3:32])([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[O:39][CH2:8][CH2:9][NH:44][CH3:42])[CH3:31])[C:24]3=[O:40])[CH:17]=2)[CH2:13][CH2:12]1
Reactant: ClCCBr
Reactant: CC#N
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O
Temperature: 83 °C
Reaction time: 16 h

Procedure:
Potassium carbonate (330 mg) and 1-bromo-2-chloroethane (0.2 mL) were added to a stirred solution of N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.1 g) in acetonitrile (5 mL). The reaction mixture was stirred under nitrogen at 83° C. for 16 h then concentrated in vacuo. The residue was treated with water and extracted into dichloromethane. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue (120 mg) was treated with 33% methylamine in ethanol (3 mL) and heated within a microwave at 100° C. for 60 minutes. The mixture was concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound as a solid (65 mg).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:15]([O:17]CC)=[CH2:16])[C:12]=3[O:13][CH3:14])[N:8]=2)[CH2:3][CH2:2]1.O.[Br:24]N1C(=O)CCC1=O>O1CCCC1>[Br:24][CH2:17][C:15]([C:11]1[C:12]([O:13][CH3:14])=[C:6]2[O:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:8][C:7]2=[C:9]([C:21]#[N:22])[C:10]=1[CH3:20])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(=O)CBr)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-methoxy-5-methyl-1,3-benzoxazole-4-carbonitrile (I-84) (2.58 g, 8.46 mmol) was dissolved in tetrahydrofuran (130 ml), water (7.7 ml) and N-bromosuccinimide (1.61 g, 8.89 mmol) were added all at a time, followed by stirring at room temperature for 1.5 hours. After the reaction, the solvent was evaporated away under reduced pressure, followed by dilution with ethyl acetate and by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography (covering) and eluted with a mixed solvent of n-hexane/ethyl acetate (2:1, v/v) to obtain the entitled compound (2.40 g, 81%) as a yellow white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].N1C[CH2:15][CH2:14][CH2:13]1.CC(C)=O>C(#N)C.CC(=O)OCC>[CH3:13][C:14]1([CH3:15])[CH2:1][C:2](=[O:3])[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)[O:11]1
Reactant: C1CCNC1
Reactant: CC(=O)c1cc(O)ccc1O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CC(=O)c2cc(O)ccc2O1
Temperature: 45 °C

Procedure:
A reaction mixture of 100 g (0.65 mol) of 2,5-dihydroxyacetophenone in 1 l of acetonitrile, 130 ml (1.55 mol) of pyrrolidine and 290 ml (3.95 mol) of acetone was heated to 45° C. for 8 h. The solvents were then stripped off in vac. and the residue was dissolved in 1 l of EA. The organic phase was washed twice with dilute hydrochloric acid, stirred with activated carbon and dried over magnesium sulfate and largely concentrated. After stirring the residue with petroleum ether and filtering off the precipitate with suction, 102 g of 2,2-dimethyl-6-hydroxychroman-4-one, m.p. 158° C., were obtained.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:37])([CH3:36])[CH:33]([CH3:35])[CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:36])([CH3:37])[CH:33]([CH3:34])[CH3:35])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 78b (1.1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.1 g, 91%).
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:41])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 73 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 73% of theory, Rf value: 0.15 (silica gel; dichloromethane/ethanol=4:1) C28H29N5O3 (483.6) ##EQU19##
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1.[CH3:35][O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:40]5[CH2:41][CH2:42][CH:37]([O:36][CH3:35])[CH2:38][CH2:39]5)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1
Reactant: COC1CCNCC1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4C3=O)cc2F)C1
Product: COC1CCN(c2ccc3c(c2)CCN(c2ccc(N4CC[C@@H](N(C)C)C4)c(F)c2)C3=O)CC1

Procedure:
Trifluoromethanesulfonic acid 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ester was reacted with 4-methoxypiperidine by method N. The product with the molecular weight of 466.60 (C27H35FN4O2) was obtained in this way; MS (ESI): 467 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6](O)=[O:7])[CH:4]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:7])[CH:4]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1cc(C(=O)O)nc2ccccc12
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Methoxyquinaldic acid (7.25 g) was dissolved in dry dimethylformamide (20 ml). N,N'-carbonyldiimidazole (5.8 g) was added, and the solution was stirred for 6 hours at room temperature. 5-Aminotetrazole (3.69 g) was added and the mixture was stirred overnight at room temperature. The solid was filtered off, washed with methanol and dissolved in dimethylformamide (50 ml) with the minimum addition of dimethylaminoethanol to effect dissolution. Water (50 ml) was added, and the solution was adjusted to pH 2 by the addition of aqueous hydrochloric acid. The solid was filtered off to give 4-methoxy-N(1H-tetrazol- 5-yl)quinaldamide, m.p. 289° (d).
Reaction SMILES: ClC1C=CC(C[C:7]([CH2:18][C:19]2([C:24]([NH:26][C@H:27]3[CH2:33][CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N:29]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:28]3=[O:46])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]2)([CH2:11][C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:8]([O-:10])=[O:9])=CC=1.[C:49](O)([C:51](F)(F)F)=O.Cl[CH2:57][Cl:58]>>[Cl:58][C:57]1[CH:51]=[CH:49][C:11]([CH2:12][O:10][C:8]([CH:7]([CH2:11][C:12]([NH:14][CH:15]([CH3:16])[CH3:17])=[O:13])[CH2:18][C:19]2([C:24]([NH:26][C@H:27]3[CH2:33][CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[N:29]([CH2:38][C:39]([OH:41])=[O:40])[C:28]3=[O:46])=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:9])=[CH:7][CH:8]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)NC(=O)CC(Cc1ccc(Cl)cc1)(CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)C(=O)[O-]
Reactant: ClCCl
Product: CC(C)NC(=O)CC(CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)O)C2=O)CCCC1)C(=O)OCc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
318 g of the 4-chlorobenzyl-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyrate obtained above was dissolved in 11 ml dichloromethane, 1.08 ml TFA was added thereto and the mixture was stirred overnight. Then the solvent was largely evaporated at reduced pressure, the remaining residue was taken up in 10 ml EA and the organic phase was washed with water until it became pH-neutral. Then the solvent was evaporated again at reduced pressure and the remaining residue was fumed off once with 5 ml of toluene. 305 mg of the title compound was obtained as a white foam resin, MS: [M+H]+: 626/628; m/z: 657, 484, 425.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.BrCCCCC1C2C(=CC=CC=2)NC=1.[CH2:29]1[C:34]2[S:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:33]=2[CH2:32][CH2:31][NH:30]1>C(#N)C>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][CH2:32][C:33]3[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[S:35][C:34]=3[CH2:29]2)=[CH:7]1
Reactant: c1ccc2c3c(sc2c1)CNCC3
Reactant: ClCCCCc1c[nH]c2ccccc12
Agent: BrCCCCc1c[nH]c2ccccc12
Solvent: CC#N
Product: c1ccc2c(CCCCN3CCc4c(sc5ccccc45)C3)c[nH]c2c1

Procedure:
A solution of 20.8 g of 3-(4-chlorobutyl)indole [or 25.2 g of 3-(4-bromobutyl)indole] and 18.9 g of 1,2,3,4-tetrahydrobenzothieno[2,3-c]pyridine in 100 ml of acetonitrile is stirred at 20° for 12 hours. The usual working up is carried out, and 2-[4-(3-indolyl)butyl]-1,2,3,4-tetrahydrobenzothieno[2,3-c]pyridine ("A"), m.p. 113°-115° is obtained.
Reaction SMILES: [C:1]([NH:5][NH2:6])(=O)[CH2:2][OH:3].[CH3:7][N:8]=[C:9]=[S:10].CO.[Na]>C(O)C>[OH:3][CH2:2][C:1]1[N:8]([CH3:7])[C:9]([SH:10])=[N:6][N:5]=1
Reactant: CN=C=S
Reactant: NNC(=O)CO
Agent: [Na]
Solvent: CCO
Solvent: CO
Product: Cn1c(S)nnc1CO
Yield: 35.9 %

Procedure:
A mixture of 9 g of glycolic acid hydrazide, 7.3 g of methyl isothiocyanate, 50 ml of methanol and 50 ml of ethanol was heated under reflux for 5 hours. Following the addition of 2.3 g of sodium metal, the mixture was further refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 150 ml of water and adjusted to pH 2.5 with phosphoric acid. The resultant crystals were collected by filtration and recrystallized from ethanol. By the above procedure there were obtained 5.2 g of the captioned compound. m.p. 199°-201° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:29])[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)[CH:12]=[N:11]1)[CH3:2].[Na].C(S)CC.Cl>CN(C=O)C.C(Cl)Cl>[CH2:30]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:29])[CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH:12]=[N:11]1)[CH3:31]
Reactant: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(OC)cc2)c1-c1ccccc1
Agent: CCCS
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(O)cc2)c1-c1ccccc1
Yield: 99 %

Procedure:
A solution of 14 g (00.33 mol) of N-[3-(diethylamino)propyl]-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamide of example 34 and 0.16 mol of the sodium salt of 1 propanethiol in 375 mL of DMF was heated at 155°-160° C. for 2 hours. The reaction was chilled and the excess thioproxide was neutralized with ethanolic HCl. The DMF solution was stripped under vacuum at 30°, dissolved in methylene dichloride, and washed with aqueous sodium carbonate, then water, and finally brine. The methylene chloride was dried over sodium sulfate and the solvent removed in vacuo to yield 13.4 g of gummy product. Seven grams of the gummy product was chromatographed on a silica gel column eluted with methanol/isopropylamine/chloroform (2:3:95) to yield 5.1 g of purified product. The residue was taken up in isopropyl acetate, washed twice with water, washed once with brine, and dried over sodium sulfate. The isopropyl acetate was evaporated in vacuo, but removal of the last traces of isopropyl acetate required extensive drying under high vacuum to yield 2.5 g of product as a glass.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+:4].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CC(C)=O>[NH2:3][C:2](=[S:1])[NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C[S-]
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
To a two-liter-round-bottomed flask fitted with an overhead stirrer, addition funnel and a condenser was added 400 ml of acetone and 85.0 g (1.12 moles) of ammonium thiocyanate. To this solution was added 140.6 g (1.00 moles) of benzoyl chloride. The resultant slurry was heated at reflux for 15 minutes and then the heat was removed and 200 ml of concentrated ammonium hydroxide was added at a rate to maintain reflux. The reaction mixture was heated at reflux for an additional 15 minutes and then cooled to room temperature. This mixture was added to 6 liters of water, and the resulting precipitate was collected by filtration and washed with 2 liters of water, then air dried and recrystallized from 1.5 liters of ethanol to give 98.5 g of the desired product as a white solid, mp 170°-171° C.